This invention relates to methods for reducing hypertension, hypertrophy, ischemia, and/or heart failure.
Cardiovascular disease is the leading cause of death in the Western world, resulting in an estimated annual death toll of more than ten million people. Such diseases, such as chronic hypertension (high blood pressure), left ventricular hypertrophy (enlargement of the heart), and myocardial ischemia (cardiac cell injury) can culminate in heart failure.
The most prevalent cardiovascular disorder that contributes to heart failure is hypertension, which is a disease largely of the vasculature. The complex pathogenesis of hypertension is not fully understood, although it is believed that functional and/or structural changes in the blood vessels are the cause.
High blood pressure is a significant health problem for several reasons. First, only one-third of the patients receiving treatment have their illness under control. Furthermore, one-third of the population in the United States are estimated to have undetected hypertension (Kaplan, (1998) Clinical Hypertension. Baltimore: Williams & Williams).
The consequences of hypertension (e.g., hypertrophy, heart failure, coronary heart disease, aortic disease, and renal failure, etc.) are widespread and can be devastating. Victims can remain asymptomatic until much damage has already occurred. Furthermore, the detrimental effects of blood pressure increase continuously as the pressure increases.
As stated above, one consequence of hypertension is generally hypertrophy. Cardiac hypertrophy is an increase in the size of the heart. In humans, hypertrophy, is the compensatory response of the myocardium (cardiac muscle) to increased work as a result of an increase in blood pressure or blood volume (hemodynamic overload). The myocardium can increase in size but is not capable of increasing cell number.
Two patterns of hypertrophy can occur depending on the stimulus, either pressure-overloaded hypertrophy or volume-overloaded hypertrophy. Pressure-overloaded hypertrophy typically occurs as a result of hypertension. The ventricles develop concentric hypertrophy, and exhibit an increased ratio of wall thickness to cavity radius.
Volume-overloaded hypertrophy generally occurs as a result of a defect in one of the valves of the heart. The ventricles develop hypertrophy with dilatation (eccentric hypertrophy), resulting in a proportionate increase in ventricular radius and wall thickness.
Initially, the development of cardiac hypertrophy is advantageous since it results in the addition of sarcomeres (contractile units), thereby reducing ventricular wall stress to normal levels (Ruwhof et al., (2000) Cardio. Res., 47:23-37). The increase in the number of sarcomeres leads to augmentation in the overall weight and size of the heart.
With prolonged hemodynamic overload, however, when the hypertrophied heart can no longer meet the increased demand in workload, the heart begins to dilate, stretching the sarcomeres and increasing the force of contraction and stroke volume. The increased stretching of the myocytes further perpetuates the hypertrophy.
Hypertrophy of the myocardium may become increasingly harmful due to the increased metabolic requirements of the enlarged heart. Molecular changes have been observed in the myocytes during development of myocardial hypertrophy. Such changes include the rapid induction of proto-oncogenes and heat shock protein genes, quantitative and qualitative changes in gene expression, and increased rate of protein synthesis (Ruwhof et al., (2000) Cardio. Res., 47:23-37). Changes that occur in the hypertrophied heart may contribute to the development of heart failure. Moreover, ischemic heart disease and arrhythmias may develop, increasing the risk of death.
A different type of heart disease occurs as a result of ischemia. Ischemia is an imbalance between the supply and demand of the heart for oxygenated blood. In addition to insufficient oxygen, ischemia is also caused by a reduced availability of nutrient substrates and inadequate removal of metabolites. In the majority of cases, myocardial ischemia occurs as a result of the narrowing or obstruction of an artery due to atherosclerosis. Four ischemic syndromes may result depending on the rate of development and severity of the arterial narrowing and the myocardial response. The ischemic syndromes are angina pectoris, myocardial infarction, chronic ischemic heart disease, and sudden cardiac death.
The cardiac diseases described above can ultimately impair cardiac function and result in heart failure. Development of heart failure usually occurs slowly, often over many years. The heart gradually loses its ability to pump blood and therefore works less efficiently. As such, heart failure is typically defined as a clinical syndrome in which the heart is unable to maintain an output sufficient for the metabolic requirements of the tissues and organs of the body.
The tissue and systemic renin-angiotensin systems play a major role in regulation of pathological cardiovascular functions, such as in hypertension (Raizada et al., (1993) Cellular and Molecular Biology of the Renin-Angiotensin System, 515-555), left ventricular hypertrophy (Lavie et al., (1991) Drugs 42:945-946), ischemic dilated cardiomyopathy, and heart failure (Raynolds et al., (1993) Lancet 342:1073-1075). The renin-angiotensin system also exists in other organs and tissues, including the heart, kidneys, prostate, brain, intestines, and the vasculature.
Normal homeostatic levels of a number of hemodynamic properties, such as blood pressure, blood volume, and vascular tone, are maintained by the renin-angiotensin system. Renin is an enzyme that was first isolated from the kidneys over a hundred years ago. Angiotensinogen is cleaved by renin to yield the inactive decapeptide angiotensin I. An enzyme is present in the vascular endothelium, especially in the lungs. The enzyme is angiotensin converting enzyme (ACE), which cleaves off two amino acids from angiotensin I to form the octapeptide, angiotensin II.
Angiotensin II is prominently involved in virtually all aspects of the renin-angiotensin activity. The angiotensin II then exerts its effects on target organs and tissues by binding its transmembrane domain G-protein coupled receptor (AT1 and/or AT2).
Binding of angiotensin II to its receptor can activate several different intracellular signal transduction pathways that use the well-known signal transducers, such as protein kinase A, protein kinase C, MAP kinase, and src (Sadoshima et al., (1993) Circ. Res. 73:413-423; Duff et al., (1995) Cardiovasc. Res. 30:511-517; Booz et al., (1995) Cardiovasc. Res. 30:537-543; Schieffer et al., (1996) Hypertension 27:476-480; Bernstein et al., (1996) Trends Cardiovasc. Med. 6:179-197).
In addition to these signal transduction pathways, angiotensin II also activates the Janus-associated kinase/signal transducer and activator of transcription (Jak/STAT) pathway. The components of the Jak/STAT pathway are present in a latent state in the cytoplasm of unstimulated cells. Binding of angiotensin II to its receptor leads to activation of Jak, a tyrosine kinase that phosphorylates STAT proteins and allows them to translocate to the nucleus. Within the nucleus, the phosphorylated STAT functions as a transcription factor (Ihle (1996) Cell 84:331-334) that recognizes and binds, in a sequence-specific fashion, to cis-regulatory elements in the promoter of target genes.
In mammals, the Jak family consists of Jak1, Jak2, Jak3, and Tyk2. Seven STAT proteins have been identified in mammalin cells, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6.
Jaks are crucial components of diverse signal transduction pathways that govern important cellular functions, including cell survival, proliferation, differentiation and apoptosis. Interfering with Jak activity may lead to the loss of a vital signal transduction pathway, thereby disrupting normal cellular processes needed for cell survival. Therefore, it is important to selectively inhibit particular Jaks that are involved in various disease states. For example, Jak2 has been suggested to be involved in the upregulation of angiotensinogen promoter activity in hypertrophy and ischemia (Mascareno E, et al. (2000) Mol. Cell. Biochem. 212:171; and Mascareno E, et al (2001) Circulation 104:1).
Inhibitors of Jaks include tyrphostins, which are a class of compounds that inhibit protein tyrosine kinases. The tyrosine kinases that are inhibited depends on the substituents that are present on the tyrphostin.
One particular tyrphostin, AG490, selectively inhibits Jak2 and has been proposed for treating cancer (Meydan N, et al. (1996) Nature 379:645). Administration of tyrphostin AG490 has been suggested to afford cardioprotection to hearts subjected to ischemia/reperfusion (Mascareno E, et al. (2000) Mol. Cell. Biochem. 212:171 and Mascareno E, et al (2001) Circulation 104:1). However, the reference does not disclose treating hypertension and/or heart failure with tyrphostin AG490.
Tyrphostin AG556 is a protein tyrosine kinase inhibitor that reduces myocardial damage due to ischemia (Altavilla D., et al, (2000) Life Sciences 67:2615). There is no indication that tyrphostin AG556 is a selective Jak2 inhibitor. The lack of selectively is a problem since it can lead to side effects.
There has been an ongoing search for effective long-term treatments for myocardial dysfunction. Currently, treatments include administering drugs, such as vasiodilators, beta-blockers, free-radical scavengers, and calcium antagonists. Another type of treatment is surgery and includes by-pass surgery and angioplasty. Virtually all of these methods have been ineffective for favorable long-term results.
Heart muscle cannot currently be regenerated. As a consequence, affected individuals must contend with damaged heart tissue for the rest of their lives. Therefore, restoring normal cardiac function to heart muscles damaged by cardiovascular disease has been a long-term goal of cardiology.
Therefore, there is an immediate need for therapeutic agents that prevent and/or reverse the damage caused by myocardial dysfunction without harming healthy cells.